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Amide derivatives as ABL modulators

a technology of amide derivatives and abl, which is applied in the direction of biocide, cardiovascular disorders, drug compositions, etc., can solve the problems of poor patient prognosis, and achieve the effects of reducing the toxicity of such inhibitory compounds, accurate targeting, and inhibiting kinase activity

Inactive Publication Date: 2005-07-07
AMBIT BIOSCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005] There remains a need for additional compounds that are effective in inhibiting kinase activity. Given the complexities of signal transduction with the redundancy and crosstalk betwee...

Problems solved by technology

Such mutations also indicate a poor prognosis for the patient.

Method used

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  • Amide derivatives as ABL modulators

Examples

Experimental program
Comparison scheme
Effect test

example a

Synthesis of Isoxazole-Amides

[0196] Compounds A1 through A240 are synthesized by methods known in the art or described herein. The structures are shown below in Table A:

TABLE ANO.STRUCTUREA1A2A3A4A5A6A7A8A9A10A11A12A13A14A15A16A17A18A19A20A21A22A23A24A25A26A27A28A29A30A31A32A33A34A35A36A37A38A39A40A41A42A43A44A45A46A47A48A49A50A51A52A53A54A55A56A57A58A59A60A61A62A63A64A65A66A67A68A69A70A71A72A73A74A75A76A77A78A79A80A81A82A83A84A85A86A87A89A90A91A92A93A94A95A96A97A98A99A100A101A102A103A104A105A106A107A108A109A110A111A112A113A114A115A116A117A118A119A120A121A122A123A124A125A126A127A128A129A130A131A132A133A134A135A136A137A138A139A140A141A142A143A144A145A146A147A148A149A150A151A152A153A154A155A156A157A158A159A160A161A162A163A164A165A166A167A168A169A170A171A172A173A174A175A176A177A178A179A180A181A182A183A184A185A186A187A188A189A190A191A192A193A194A195A196A197A198A199A200A201A202A203A204A205A206A207A208A209A210A211A212A213A214A215A216A217A218A219A220A221A222A223A224A225A226A227A228A229A...

example b

Exemplary Synthesis of Isoxazole-Amides

[0197]

[0198] In a 40 mL vial, 1 mL of thionyl chloride was added to 0.2 mmol para-substituted phenylacetic acid. The vial was capped and stirred at 80° C. for approximately three hours. The completion of the reaction was checked by TLC. The excess thionyl chloride was removed in vacuo. The residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (0.2 mmol) and DIEA (0.2 mmol). The reaction was stirred overnight at 45° C. The solvent was removed under vacuum and the product was purified by HPLC.

Synthesis of Compound B1: N-(3-tert-butylisoxazol-5-yl)-2-(4-(benzyloxy)phenyl)acetamide

[0199]

[0200] (4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was stirred with 1 mL of thionyl chloride at 80° C. for approximately three hours. The completion of the reaction was checked by TLC. Excess thionyl chloride was removed in vacuo, the residue was dissolved in dichloromethane and added to a mixture of 3-ter...

example c

of thiazole-amides

Synthesis of Compound C1: 2-(4-(benzyloxy)phenyl)-N-(5-methylthiazol-2-yl)acetamide

[0202]

[0203] Compound C1 was prepared in strict analogy to compound B1 using 2-amino-5-methylthiazole as starting material instead of 3-tert-butyl-isoxazol-5-ylamine.

[0204] Compounds C2 through C6 were synthesized in a manner analogous to Compound C1 using similar starting materials and reagents. The structures are shown below in Table C:

TABLE CNO.CHEMICAL STRUCTUREC1C2C3C4C5C6

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PUM

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Abstract

The invention provides methods and compositions for treating conditions mediated by abl wherein derivatives of amide compounds are employed. The invention also provides methods of using the compounds and / or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 520,273, filed Nov. 13, 2003, U.S. Provisional Application No. 60 / 527,094, filed Dec. 3, 2003, U.S. Provisional Application No. 60 / 531,243, filed Dec. 18, 2003, and U.S. Provisional Application No. 60 / 531,082, filed Dec. 18, 2003, the contents of which are incorporated herein by reference in their entirety.BACKGROUND [0002] Protein kinases (PKs) play a role in signal transduction pathways regulating a number of cellular functions, such as cell growth, differentiation, and cell death. PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins, and can be conveniently broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). Growth factor receptors with PTK activity are known as receptor tyrosine kinases. Protein receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberran...

Claims

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Application Information

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IPC IPC(8): A61KA61K31/42A61K31/47A61K31/4709A61K31/4745A61K31/503A61K31/517A61K31/519A61K31/52C07D215/38C07D231/12C07D231/40C07D261/06C07D261/08C07D261/14C07D261/18C07D277/46C07D277/82C07D405/12C07D413/00C07D413/02C07D413/04C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D471/06C07D473/10C07D487/04C07D495/04C07D513/04
CPCA61K31/42C07D513/04C07D231/40C07D261/08C07D261/14C07D261/18C07D277/46C07D277/82C07D405/12C07D413/04C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D471/06C07D487/04C07D495/04C07D231/12A61P11/00A61P11/08A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00A61P9/00A61P9/10Y02A50/30
Inventor GROTZFELD, ROBERTPATEL, HITESHMEHTA, SHAMALMILANOV, ZDRAVKOLAI, ANDILIYLOCKHART, DAVID
Owner AMBIT BIOSCIENCES
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